Category Archives: C. diff. prevention clinical trials

DAV132 is a first-in-class product to protect the microbiome during antibiotic treatments and prevent Clostridium difficile infections.

French biotech Da Volterra is developing products to fight the rapidly rising rates of antibiotic resistance. During a Phase I study, the company’s medical device, DAV132, was used with the antibiotic, moxifloxacin, and successfully protected the intestinal microbiota from antibiotic residues. Overall, the product managed to reduce exposure of the microbiota to the antibiotic by 99% and maintain 97.8% of the microbiome’s genetic richness without affecting the drugs therapeutic efficacy.

In a randomized, controlled clinical trial performed in 44 healthy human volunteers, DAV132 was used in association with moxifloxacin, a widely used fluoroquinolone antibiotic. It was demonstrated that DAV132 is able to effectively capture residual antibiotics in the colon and reduce their concentration to very low levels. DAV132 reduced exposure of the intestinal microbiota to moxifloxacin by 99%. Meanwhile the plasma concentration of the antibiotic was essentially unaffected by the co-administration DAV132, meaning that its therapeutic efficacy will be maintained.

The ability of DAV132 to protect the intestinal microbiome was explored by identifying changes in bacterial gene richness as well as a detailed statistical analysis of the evolution of bacterial species throughout the study. In volunteers who received moxifloxacin alone, gene richness was drastically diminished to 54.6% of baseline after antibiotic treatment and failed to return to baseline even one month after treatment; 39% of bacterial species identified in the intestinal microbiota were affected. The co-administration of DAV132 with moxifloxacin largely protected the intestinal microbiome from disruption (97.8% of baseline for bacterial gene richness, and 93% of bacterial species protected).

The primary endpoints for the study were fully achieved and DAV132 showed an excellent tolerability profile.

Annie Ducher MD, Chief Medical Officer of Da Volterra, declared: “This clinical study is indicative of the potential of DAV132 to become one of the first preventative solutions to protect the intestinal microbiome and further avoid the detrimental consequences of antibiotic treatments, such as Clostridium difficile infections, for patients. We look forward to advancing the development of DAV132 in a pivotal patient study in 2018.”

Jean de Gunzburg PhD, Chief Scientific Officer of Da Volterra, added: “This study constitutes the first scientific demonstration of the protection of the intestinal microbiome from dysbiosis caused by a fluoroquinolone antibiotic treatment; our data suggests that this effect should be extendable to many different antibiotics from several therapeutic classes. The metagenomics analysis is outstanding and thoroughly convincing that DAV132 is highly effective at protecting the commensal bacteria in the intestines.”

The results are available under the reference: Gunzburg et al. Protection of the human gut microbiome from antibiotics. The Journal of Infectious Diseases, jix604, https://doi.org/10.1093/infdis/jix604.

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About DAV132:
With a novel and unique mechanism of action, DAV132 is a product candidate aiming toprotect the intestinal microbiome from the side effects of antibiotics, hence preventing the onset of C. difficile infections. DAV132 is an adsorbent with a proprietary coating with colon targeted delivery. DAV132 has been tested in four Phase 1 clinical studies with no adverse safety events. DAV132 is currently entering a Phase 2 clinical trial.

About Da Volterra:
Da Volterra is a biopharmaceutical company based in France that develops new strategies aimed at protecting the intestinal microbiome from the deleterious effects of antibiotics, and preventing multi-resistant and life-threatening infections. Da Volterra’s innovative approaches promise a substantial medical progress to combat deadly pathogens. http://www.davolterra.com

(January 2018)

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Sanofi Pasteur SA Pharmaceutical company announced on Friday, December 1, 2017 that it had ended development of an experimental vaccine for Clostridium difficile infection, after an early look at late-stage trial results indicated a low probability for success.

About three million Americans are infected annually with the bacterium – also known as C. diff – ———

The move marks the second blow in a week to Sanofi’s vaccine program after the Paris-based company on Wednesday said use of its new dengue vaccine will be strictly limited due to evidence it can worsen the disease in people who have not previously been exposed to the mosquito-borne virus.

Sanofi’s Dengvaxia vaccine is the world’s first approved shot for preventing dengue infection, which kills about 20,000 people a year and infects hundreds of millions.

The company said in a statement that all data from vaccinated volunteers in the C. diff trial will continue to be analyzed for more information and shared with the scientific community.

As many as 30,000 Americans die each year from the bacterium, usually after recurrences of infection. The infections are typically the result of taking antibiotics, which wipe out friendly bacteria in the colon that normally keep C. diff under control.

Sanofi said it will continue to focus on six other vaccine projects in development.

Positive Topline Data from Open-Label Phase 2 Trial of RBX2660 in Recurrent Clostridium
difficile to be Presented for First Time

Rebiotix Inc., a clinical-stage microbiome company focused
on harnessing the power of the human microbiome to treat challenging diseases, today announced that three posters highlighting RBX2660 clinical and microbiome data will be featured at ID Week™ 2017 in San Diego, Oct. 4th to the 8th.

The posters describe clinical findings that highlight the key changes to
the human microbiome profiles of patients who received RBX2660, Rebotix’s Phase 3 drug candidate.

For the first time, researchers will discuss findings from the open-label Phase 2 trial of RBX2660 for the prevention of recurrent Clostridium difficile (C. diff.) infection. Data indicated that RBX2660 was well tolerated and achieved the primary efficacy endpoint of preventing C. diff. recurrence; patients treated with RBX2660 exhibited a treatment success rate of 78.8% compared with a historical control of 51.8% (p<0.0001, N=242). These results demonstrate a 55% reduction in recurrence for those patients treated with RBX2660 compared to the historical controls reflecting standard-of-care antibiotics today.

RBX2660 is currently being evaluated in a multinational Phase 3 clinical trial for the prevention of recurrent C. diff. Researchers will also be presenting two posters on the microbiome analyses of the Phase 2B randomized, placebo-controlled, double-blind clinical trial of RBX2660. The analyses, utilizing leading edge genomic sequencing technology to measure the patient’s microbiome, provide measurable evidence of RBX2660’s rehabilitative effect on human microbiome profiles of patients who were successfully treated with Rebiotix’s microbiota drug technology.

“The clinical potential of RBX2660 has been highlighted in multiple trials, including our recently
completed open-label Phase 2 study, and the data being presented at ID Week enables us to more fully understand RBX2660’s ability to rehabilitate a dysbiotic intestinal microbiome,” commented Lee Jones, president and CEO of Rebiotix. “These findings are important in that not only can we observe the clinical 2 effect of RB X2660, such as in the open-label Phase 2 study, but by analyzing the microbiota of RBX2660-treated patients, we can see how the microbiome changes in response to RBX2660 treatment and how those changes correlate to treatment success and to the microbiomes of healthy individuals.”

The first poster (#1863; to be presented Friday, Oct. 6th), titled RBX2660 is Safe, Superior to Antibiotic- Treated Controls for Preventing Recurrent Clostridium difficile, and May Rehabilitate Patient Microbiomes: Open Label Trial Results, reported data from an open-label Phase 2 study of RBX2660 that included 242 subjects. Data from the study indicated that RBX2660’s efficacy in preventing recurrent Clostridium difficile infection (rCDI) was higher (78.8%) than CDI-free rates in the Historical Control Group (51.8%, p<0.0001). The reduction in recurrence of C. diff between these two arms is approximately 55%. Moreover, the safety profile of RBX2660 was consistent with results from previous clinical trials, and microbiota analysis suggested that RBX2660 may rehabilitate patient microbiota as RBX2660-treated subjects’ microbiomes were significantly altered compared to baseline and more closely resembled the RBX2660 microbiome profile than at baseline (p<0.05 by Dirichlet multinomial Wald-type pairwise hypothesis test).

The second poster (#1267; to be presented Saturday, Oct, 7th), titled Successful Response to
Microbiota-Based Drug RBX2660 in Patients with Recurrent Clostridium Difficile Infection is Associated with More Pronounced Alterations in Microbiome Profile, involved an analysis of 58 patients whose stool samples were collected in the randomized Phase 2B clinical trial to determine the effect of RBX2660 on rCDI patient microbiomes. 16s RNA sequencing analyses of patients’ microbiomes indicated that RBX2660 treatment shifted the relative microbiome densities, with taxa-specific increase in Bacteroidia, Clostridia, and decrease in Gamma-proteobacteria abundance. Importantly, a larger shift from baseline microbiome was seen in responders to RBX2600 compared to non-responders, and RBX2660 treatment appears to increase microbiome diversity.

The third poster (#1870; to be presented Saturday, Oct. 7th), titled Microbiome Profile is Distinct in Patients with Successful Response to Microbiota-Based Drug RBX2660 Relative to Placebo Responders involved a sub-analysis of 57 patients who participated in the randomized Phase 2B clinical trial of RBX2660. 16s rRNA sequencing analysis was used to compare the microbiome changes from baseline of patients classified as responders to RBX2660 vs placebo. Investigators determined that RBX2660 treatment for rCDI is associated with greater changes in patient microbiomes than placebo treatment. Notably, at 7, 30 and 60 days, microbiomes from RBX2660-treated patients had high Kullback-Leibler divergence from baseline and significantly different means from baseline (p<0.001). Further, active responders trended toward higher Bacteroides and lower Gamma-proteobacteria and Bacilli after treatment, both of which are characteristic of a healthier microbiome. According to the 3 researchers, these changes are consistent with the hypothesis that RBX2660 can restore a healthier microbiome in rCDI patients.

“These data support that ribaxamase can maintain the balance of the gut microbiome and thereby prevent opportunistic infections like CDI during IV beta-lactam treatment,” said lead study author John Kokai-Kun, PhD, of Synthetic Biologics, Inc., Rockville, MD.

“Ribaxamase also protected the diversity of the gut microbiome and reduced the emergence of antibiotic resistance in ceftriaxone-treated patients,” he said.

CDI represent an “urgent threat” but there are no FDA-approved drugs or vaccines to prevent infections, Dr. Kokai-Kun noted.

“SYN-004 (ribaxamase) is a beta-lactamase designed to be orally administered with IV beta-lactam antibiotics and remain localized in the intestine to degrade antibiotics excreted into the intestine,” he said. “This is expected to protect the gut microbiome from disruption thus preventing deleterious effects including, CDI, colonization by opportunistic pathogens and emergence of antibiotic resistance in the gut microbiome.”

“Ribaxamase was well tolerated and not systemically absorbed in Phase 1 studies and efficiently degraded ceftriaxone excreted into the human intestine while not altering the plasma pharmacokinetics of ceftriaxone in Phase 2a studies,” he told the IDWeek audience.

Data from 412 patients (man age 70 years) in the intention-to-treat population “enriched for higher risk for CDI” were hospitalized for ≥5 days of IV ceftriaxone for treatment lower respiratory tract infections,” Dr. Kokai-Kun said. Patients were randomly assigned 1:1 to receive oral ribaxamase 150mg four times daily or placebo during IV ceftriaxone treatment and for an additional 72 hours.

“Fecal samples were collected at pre-specified points for determination of colonization by opportunistic pathogens and to examine changes in the gut microbiome,” Dr Kokai-Kun said. Patients were monitored for 6 weeks for CDI, defined as diarrhea plus the presence of C. difficile toxin.

Study participants saw a 71% relative risk reduction in CDI (P=0.045) and a statistically significant 44% relative risk reduction in new colonization by vancomycin-resistant enterococci (P=0.0002). Moreover, the respiratory infection was cleared in ~99% of cases demonstrating that concomitant ribaxamase did not impact the cure rate of ceftriaxone.

For continuous infectious disease news coverage from the IDWeek 2017, check back to MPR’s IDWeek page for the latest updates.

On May 11, 2017 Synthetic Biologics, Inc. a late-stage clinical company developing therapeutics that preserve the microbiome to protect and restore the health of patients, announced that the U.S. Food and Drug Administration (FDA) has granted a Breakthrough Therapy Designation for SYN-004 (ribaxamase)for the prevention of Clostridium difficile infection.

SYN-004 (ribaxamase) is the Company’s first-in-class oral enzyme designed to protect the gut microbiome from disruption caused by certain intravenous (IV) beta-lactam antibiotics.

The Breakthrough Therapy Designation is based on data from the successful Phase 2b clinical trial of ribaxamase, which met its primary endpoint of significantly reducing CDI. FDA Breakthrough Therapy Designation is intended to expedite development and review timelines when preliminary clinical evidence indicates that a drug may demonstrate substantial improvement on one or more clinically significant endpoints over available therapies for serious or life threatening diseases. If approved by the FDA, SYN-004 (ribaxamase) would be the first available drug designed to prevent Clostridium difficile infection by protecting the gut microbiome from antibiotic-mediated dysbiosis.

“We are delighted by the FDA’s recognition of ribaxamase’s potential to prevent CDI, and the dire need to fill the current void of an approved intervention,” said Jeffrey Riley, President and Chief Executive Officer. “Following this announcement, we have been asked and anticipate requesting a Type-B multidisciplinary meeting with the Agency for a comprehensive discussion on the overarching, high-level drug development plan and pathway to licensure for ribaxamase. We look forward to working closely with the FDA throughout the development and review process and remain dedicated to bringing this potentially paradigm-shifting approach to antibiotic therapy to patients in critical need.”

Live Broadcast On Tuesday, May 16th Join us with our guest, Dr. Joseph Sliman, MD, MPH, Chief Medical Officer of Synthetic Biologics. Dr. Sliman will be discussing the protection of the natural gut microbiome from the unintended consequences of intravenous (IV) antibiotics which are excreted into the gut is expected to protect against opportunistic enteric infections. Synthetic Biologics is developing two microbiome-focused drug candidates in Phase 3 development including, SYN-004 (ribaxamase) which is designed to protect the gut microbiome by degrading certain IV beta-lactam antibiotics for the prevention of Clostridium difficile infection (CDI), pathogenic
overgrowth and the emergence of antimicrobial resistance, and SYN-010 which is intended to reduce the impact of methane producing organisms in the gut microbiome to treat an underlying cause of irritable bowel syndrome with constipation (IBS-C).

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To learn more about Synthetic Biologics, please click on the link provided below

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